Use of s1p receptor modulator

ABSTRACT

Use of an S1P receptor modulator in the treatment or prevention of a disease or condirion dependent on brain-derived neurotrophic factor (BDNF) expression.

The present invention relates to the use of an S1P receptor modulator inthe treatment or prevention of a peripheral nervous system disorder,such as Guillan Barre syndrome (GBS)

One of the neurotrophic factors, a brain-derived neurotrophic factor(hereinafter, often referred to as BDNF), is a protein, which isprovided from target cells or neurons and glial cells and Schwann cellsin the living body, and shows activities to maintain the survival anddifferentiation of neurons.

It has now been surprisingly shown that S1P receptor modulators caninduce BDNF production.

BDNF has been known as a therapeutic agent for treatment ofneurodegenerative diseases (e.g., ALS) or diabetic peripheralneuropathy. BDNF has also been described to be useful as a therapeuticagent for treatment of diabetic mellitus.

Therefore, by inducing BDNF production (or stimulating BDNF expression)S1P receptor modulators can be employed to treat such conditionsaffected by BDNF, i.e. conditions which can be treated, delayed orprevented by the increased expression of BDNF.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the induction of brain-derived neurotrophic factor (BDNF)in the cortex of female DA rats after a 9-day treatment period with 0.3mg/kg/d FTY720 measured by Western blot. Shown on the y-axis is therelative intensity of BDNF signal of animals treated with FTY720 vscontrol animals that had received vehicle (i.e., ratio of signal fromFTY720-treated rats divided by signal from vehicle-treated rats, n=3rats/group). On the x axis, the first two bars come from the frontalcortex, the second two from the parietal cortex and in each case thewhite bar represents the vehicle treated animals and the black barrepresents the FTY720 treated animals.

FIG. 2 Similar to FIG. 1, FIG. 2 shows the induction of BDNF in thecortex of female DA rats after a 9-day treatment period, but usingmultiple doses of FTY720. N=3 animals each were treated with eithervehicle, 0.1 mg/kg/d FTY720, 0.3 mg/kg/d FTY720 or 1 mg/kg/d FTY720. Thetop panel (FIG. 2A) shows the induction of BDNF in the pre-frontalcortex of female DA rats. The bottom panel (FIG. 2B) shows the inductionof BDNF in the parietal cortex of female DA rats.

FIG. 3 shows the results of a study wherein neuronal cultures wereestablished using neurons from different brain regions. The cells werecultured for a total period of 21 days and FTY720-P was added for thelast 6 days of the culture period. As with the results shown in FIGS. 1and 2, BDNF levels were measured by Western blot and normalised to thelevel observed in the vehicle control. FIG. 3A shows the results of theassay in CTX neurons. FIG. 3B shows the results of the assay in STRneurons. FIG. 3C shows the results of the assay in HIP neurons.

FIG. 4 shows the results of a study similar to that shown in FIG. 3, butusing a broader range of concentrations of FTY720P (all in nM). FIG. 4Ashows the results of the assay in CTX neurons. FIG. 4B shows the resultsof the assay in HIP neurons.

FIG. 5 shows the mean BDI-II (Beck Depression inventory, second edition)scores of patients participating in a 6 month, placebo controlled PhaseII trial of FTY720 in 281 patients having relapsing multiple sclerosis,at the beginning and end of such study (i.e., at t=0 months and t =6months).

FIG. 6 shows the changes from baseline in the BDI-II scores of the 281patients in the study referred to above in the description of FIG. 5.

S1P receptor modulators are typically sphingosine analogues, such as2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives,e. g. a compound comprising a group of formula Y.

Sphingosine-1 phosphate (hereinafter “S1P”) is a natural serum lipid.Presently there are eight known S1P receptors, namely S1 P1 to S1P8, S1P receptor modulators are typically sphingosine analogues, such as2-substituted 2-amino-propane-1,3-diol or 2-amino-propanol derivatives,e. g. a compound comprising a group of formula Y

wherein Z is H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, phenylsubstituted by OH, C₁₋₆alkyl substituted by 1 to 3 substituents selectedfrom the group consisting of halogen, C₃₋₈cycloalkyl, phenyl and phenylsubstituted by OH, or CH₂—R₄, wherein R_(4z) is OH, acyloxy or a residueof formula (a)

wherein Z₁ is a direct bond or O, preferably O;

each of R_(5z) and R_(6z), independently, is H, or C₁₋₄alkyl optionallysubstituted by 1, 2 or 3 halogen atoms;

R_(1z) is OH, acyloxy or a residue of formula (a); and each of R_(2z)and R_(3z) independently, is H, C₁₋₄alkyl or acyl.

Group of formula Y is a functional group attached as a terminal group toa moiety which may be hydrophilic or lipophilic and comprise one or morealiphatic, alicyclic, aromatic and/or heterocyclic residues, to theextent that the resulting molecule wherein at least one of Z and R_(1z)is or comprises a residue of formula (a), signals as an agonist at oneof more sphingosine-1-phosphate receptor.

S1P receptor modulators are compounds which signal as agonists at one ormore sphingosine-1 phosphate receptors, e.g. S1 P1 to S1P8. Agonistbinding to a S1 P receptor may e.g. result in dissociation ofintracellular heterotrimeric G-proteins into Gα-GTP and Gβγ-GTP, and/orincreased phosphorylation of the agonist-occupied receptor andactivation of downstream signaling pathways/kinases.

The binding affinity of S1P receptor modulators to individual human S1Preceptors may be determined in following assay:

S1P receptor modulator activities of compounds are tested on the humanS1P receptors S1P₁, S1P₂, S1P₃, S1P₄ and S1P₅, Functional receptoractivation is assessed by quantifying compound induced GTP [γ-³⁵S]binding to membrane protein prepared from transfected CHO or RH7777cells stably expressing the appropriate human S1P receptor. The assaytechnology used is SPA (scintillation proximity based assay). Briefly,DMSO dissolved compounds are serially diluted and added to SPA-bead(Amersham-Pharmacia) immobilised S1P receptor expressing membraneprotein (10-20 μg/well) in the presence of 50 mM Hepes, 100 mM NaCl, 10mM MgCl₂, 10 μM GDP, 0.1% fat free BSA and 0.2 nM GTP [γ-³⁵S] (1200Ci/mmol). After incubation in 96 well microtiterplates at RT for 120min, unbound GTP [γ-³⁵S] is separated by a centrifugation step.Luminescence of SPA beads triggered by membrane bound GTP [γ-³⁵S] isquantified with a TOPcount plate reader (Packard). EC₅₀s are calculatedusing standard curve fitting software. In this assay, the S1P receptormodulators preferably have a binding affinity to S1P receptor <50 nM.

Preferred S1P receptor modulators are e.g. compounds which in additionto their S1P binding properties also have accelerating lymphocyte homingproperties, e.g. compounds which elicit a lymphopenia resulting from are-distribution, preferably reversible, of lymphocytes from circulationto secondary lymphatic tissue, without evoking a generalizedimmunosuppression. Naïe cells are sequestered; CD4 and CD8 T-cells andB-cells from the blood are stimulated to migrate into lymph nodes (LN)and Peyer's patches (PP).

The lymphocyte homing property may be measured in following BloodLymphocyte Depletion assay:

A S1P receptor modulator or the vehicle is administered orally by gavageto rats. Tail blood for hematological monitoring is obtained on day—1 togive the baseline individual values, and at 2, 6, 24, 48 and 72 hoursafter application. In this assay, the S1P receptor agonist or modulatordepletes peripheral blood lymphocytes, e.g. by 50%, when administered ata dose of e.g. <20 mg/kg.

Examples of appropriate S1P receptor modulators are, for example:

Amino alcohol compounds of formula I

wherein X is O, S, SO or SO₂;

R₁ is halogen, trihalomethyl, OH, C₁₋₇alkyl, C₁₋₄alkoxy,trifluoromethoxy, phenoxy, cyclohexylmethyloxy, pyridylmethoxy,cinnamyloxy, naphthylmethoxy, phenoxymethyl, CH₂—OH, CH₂—CH₂—OH,C₁₋₄alkylthio, C₁₋₄alkylsulfinyl, C₁₋₄alkylsulfonyl, benzylthio, acetyl,nitro or cyano, or phenyl, phenylC₁₋₄alkyl or phenyl-C₁₋₄alkoxy eachphenyl group thereof being optionally substituted by halogen, CF₃,C₁₋₄alkyl or C₁₋₄alkoxy;

R₂ is H, halogen, trihalomethyl, C₁₋₄alkoxy, C₁₋₇alkyl, phenethyl orbenzyloxy;

R₃H, halogen, CF₃, OH, C₁₋₇alkyl, C₁₋₄alkoxy, benzyloxy, phenyl orC₁₋₄alkoxymethyl; each of R₄ and R₅, independently is H or a residue offormula (a)

wherein each of R₈ and R₉, independently, is H or C₁₋₄alkyl optionallysubstituted by halogen; and

n is an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof;

or a compound of formula II

wherein

-   -   R_(1a) is halogen, trihalomethyl, C₁₋₄alkyl, C₁₋₄alkoxy,        C₁₋₄alkylthio, C₁₋₄alkylsulifinyl, C₁₋₄alkyl-sulfonyl, aralkyl,        optionally substituted phenoxy or aralkyloxy;    -   R_(2a) is H, halogen, trihalomethyl, C₁₋₄alkyl, C₁₋₄alkoxy,        aralkyl or aralkyloxy;    -   R_(3a) is H, halogen, CF₃, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkylthio        or benzyloxy;    -   R_(4a) is H, C₁₋₄alkyl, phenyl, optionally substituted benzyl or        benzoyl, or lower aliphatic C₁₋₅acyl;    -   R_(5a) is H, monohalomethyl, C₁₋₄alkyl, C₁₋₄alkoxy-methyl,        C₁₋₄alkyl-thiomethyl, hydroxyethyl, hydroxypropyl, phenyl,        aralkyl, C₂₋₄alkenyl or -alkynyl;    -   R_(6a) is H or C₁₋₄alkyl;    -   R_(7a) is H, C₁₋₄alkyl or a residue of formula (a) as defined        above,    -   X, is O, S, SO or SO₂; and    -   n_(a) is an integer of 1 to 4;

or a pharmaceutically acceptable salt thereof.

With regard to the compounds of formulae (I) and (II), the term“halogen” encompasses fluorine, chlorine, bromine and iodine. The term“trihalomethyl group” encompasses trifluoromethyl and trichloromethyl.“C₁₋₇ alkyl” encompasses straight-chained or branched alkyl, e.g.methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl orheptyl. The phrase “substituted or unsubstituted phenoxy group”encompasses those that have, at any position of its benzene ring, ahalogen atom, such as fluorine, chlorine, bromine and iodine,trifluoromethyl, C₁₋₄alkyl or C₁₋₄alkoxy. The term “aralkyl group” as in“aralkyl group” or “aralkyloxy group” encompasses benzyl,diphenylmethyl, phenethyl and phenylpropyl. Any alkyl moiety as presentin “C₁₋₄alkoxy”, “C₁₋₄alkylthio”, “C₁₋₄alkylsulfinyl” or“C₁₋₄alkylsulfonyl encompasses straight-chained or branched C₁₋₄alkyl,e.g. methyl, ethyl, propyl, isopropyl or butyl. The phrase “substitutedor unsubstituted aralkyl group” encompasses those that have, at anyposition of its benzene ring, a halogen atom, such as fluorine,chlorine, bromine and iodine, trifluoromethyl, lower alkyl having 1-4carbon atoms, or lower alkoxy having 1-4 carbon atoms.

Other compounds of formula I are compounds of formula Ia

wherein

R₂, R₃, R₄, R₅ and n are as defined above; and

R₆ is hydrogen, halogen, C₁₋₇alkyl, C₁₋₄alkoxy or trifluoromethyl.

Further preferred compounds of formula (Ia) are those wherein R₃ ischlorine, e.g.,2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethyl-propane-1,3-diol,2-amino-2-[4-(3-benzyloxyphenoxy)-2-chlorophenyl]propyl-1,3-propane-diolor2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]propyl-1,3-propane-diolor a pharmacological salts or hydrates thereof and theirs correspondingphosphate derivatives. Also exemplified is phosphoric acidmono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester.The phosphoric acidmono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]estercan be prepared enantiomerically pure by the procedures described in WO2005/021503.

Other compounds of formula are compounds of formula (IIa)

wherein

-   -   Y is O or S; and    -   R_(2a), R_(3a), R_(5a), R_(7a) and n are as defined above.

Preferred compounds of formula (IIa) are those wherein R₃ is chlorine,e.g.,2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutane-1-ol;the corresponding phosphoric acidmono-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-methylbutyl]ester;2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethylbutane-1-ol;and the corresponding phosphoric acidmono-2-amino-4-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]-2-ethylbutyl]ester.

Compounds of formulae I and H are known and are disclosed e.g. inWO03/029205, WO 03/029184 and WO04/026817, respectively, thephosphorylated derivatives being disclosed e.g. in WO04/074297, thecontents of which being incorporated herein by reference in theirentirety. Compounds of formulae I and II may be prepared as disclosed inabove cited references.

Phosphorylated derivatives of compounds of formula (I), e.g., phosphoricacidmono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester,can be prepared utilizing the procedures for synthesizing phosphorylatedcompounds described e.g., in WO 2005/021503 (see, e.g., pages 11 and12). Optically active compounds of structural formula (I) andphosphorylated derivatives thereof, in particular of formula (Ia) can beprepared in high purity utilizing the procedure described, e.g., inHinterding et al., Synthesis, Vol. 11, pp. 1667-1670 (2003). As anexample, an optically active compound of structural formula (Ia),phosphoric acidmono-2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-propyl]ester,can be prepared as described in the scheme below utilizing theprocedures of Hinterding et al. (2003) supra.

Also included are compounds as disclosed in EP627406A1, e.g. a compoundof formula III

wherein R₁ is a straight- or branched (C₁₂₋₂₂)chain

-   -   which may have in the chain a bond or a hetero atom selected        from a double bond, a triple bond, O, S, NR₆, wherein R₆ is H,        C₁₋₄alkyl, aryl-C₁₋₄alkyl, acyl or (C₁₋₄alkoxy)carbonyl, and        carbonyl, and/or        -   which may have as a substituent C₁₋₄alkoxy, C₂₋₄alkenyloxy,            C₂₋₄alkynyloxy, arylC₁₋₄alkyl-oxy, acyl, C₁₋₄alkylamino,            C₁₋₄alkylthio, acylamino, (C₁₋₄alkoxy)carbonyl,            (C₁₋₄alkoxy)-carbonylamino, acyloxy, (C₁₋₄alkyl)carbamoyl,            nitro, halogen, amino, hydroxyimino, hydroxy or carboxy; or

R₁ is

-   -   a phenylalkyl wherein alkyl is a straight- or branched        (C₈₋₂₀)carbon chain; or    -   a phenylalkyl wherein alkyl is a straight- or branched        (C₁₋₃₀)carbon chain wherein said phenylalkyl is substituted by    -   a straight- or branched (C₅₋₂₀)carbon chain optionally        substituted by halogen,    -   a straight- or branched (C₆₋₂₀)alkoxy chain optionally        substituted by halogen,    -   a straight- or branched (C₆₋₂₀)alkenyloxy,    -   phenyl-C₁₋₁₄alkoxy, halophenyl-C₁₋₄alkoxy,        phenyl-C₁₋₁₄alkoxy-C₁₋₁₄alkyl, phenoxy-C₁₋₄alkoxy or        phenoxy-C₁₋₄alkyl,    -   cycloalkylalkyl substituted by C₆₋₂₀alkyl,    -   heteroarylalkyl substituted by C₆₋₂₀alkyl,    -   heterocyclic C₆₋₂₀alkyl or    -   heterocyclic alkyl substituted by C₂₋₂₀alkyl,

and wherein

the alkyl moiety may have

-   -   in the carbon chain, a bond or a heteroatom selected from a        double bond, a triple bond, O, S, sulfinyl, sulfonyl, or NR₆,        wherein R₆ is as defined above, and    -   as a substituent C₁₋₄alkoxy, C₂₋₄alkenyloxy, C₂₋₄alkynyloxy,        arylC₁₋₄alkyloxy, acyl, C₁₋₄alkyl-amino, C₁₋₄alkylthio,        acylamino, (C₁₋₄alkoxy)carbonyl, (C₁₋₄alkoxy)carbonylamino,        acyloxy, (C₁₋₄alkyl)carbamoyl, nitro, halogen, amino, hydroxy or        carboxy, and

each of R₂, R₃, R₄ and R₅, independently, is H, C₁₋₄ alkyl or acyl

or a pharmaceutically acceptable salt or hydrate thereof;

-   -   Compounds as disclosed in EP 1002792A1 e.g. a compound of        formula IV

wherein m is 1 to 9 and each of R′₂, R′₃, R′₄ and R′₅, independently, isH, C₁₋₆alkyl or acyl,

or a pharmaceutically acceptable salt or hydrate thereof;

-   -   Compounds as disclosed in EP0778263 A1, e.g. a compound of        formula V

wherein W is H; C₁₋₆alkenyl, C₂₋₆alkenyl or C₂₋₆alkynyl; unsubstitutedor by OH substituted phenyl; R″₄O(CH₂)_(n); or C₁₋₆alkyl substituted by1 to 3 substituents selected from the group consisting of halogen,C₃₋₈cycloalkyl, phenyl and phenyl substituted by OH;

X is H or unsubstituted or substituted straight chain alkyl having anumber p of carbon atoms or unsubstituted or substituted straight chainalkoxy having a number (p-1) of carbon atoms, e.g. substituted by 1 to 3substitutents selected from the group consisting of C₁₋₆alkyl, OH,C₁₋₅alkoxy, acyloxy, amino, C₁₋₆alkylamino, acylamino, oxo,haloC₁₋₆alkyl, halogen, unsubstituted phenyl and phenyl substituted by 1to 3 substituents selected from the group consisting of C₁₋₆alkyl, OH,C₁₋₆alkoxy, acyl, acyloxy, amino, C₁₋₆alkylamino, acylamino,haloC₁₋₆alkyl and halogen; Y is H, C₁₋₆alkyl, OH, C₁₋₆alkoxy, acyl,acyloxy, amino, C₁₋₆alkylamino, acylamino, haloC₁₋₆alkyl or halogen, Z₂is a single bond or a straight chain alkylene having a number or carbonatoms of q,

each of p and q, independently, is an integer of 1 to 20, with theproviso of 6≦p+q≦23, m′ is 1, 2 or 3, n is 2 or 3,

each of R″₁, R″₂, R^(″) ₃ and R″₄, independently, is H, C₁₋₄alkyl oracyl,

or a pharmaceutically acceptable salt or hydrate thereof,

-   -   Compounds as disclosed in WO02/18395, e.g. a compound of formula        VIa or VIb

wherein X_(a) is O, S, NR_(1s) or a group —(CH₂)_(na)—, which group isunsubstituted or substituted by 1 to 4 halogen; n, is 1 or 2, R_(1s) isH or (C₁₋₄)alkyl, which alkyl is unsubstituted or substituted byhalogen; R_(1a) is H, OH, (C₁₋₄)alkyl or O(C₁₋₄)alkyl wherein alkyl isunsubstituted or substituted by 1 to 3 halogen; is H, OH or (C₁—)alkyl,wherein alkyl is unsubstituted or substituted by halogen; each R_(2a) isindependently selected from H or (C₁₋₄)alkyl, which alkyl isunsubstituted or substituted by halogen; R_(3a) is H, OH, halogen orO(C₁₋₄)alkyl wherein alkyl is unsubstituted or substituted by halogen;and R_(3b) is H, OH, halogen, (C₁₋₄)alkyl wherein alkyl is unsubstitutedor substituted by hydroxy, or O(C₁₋₄)alkyl wherein alkyl isunsubstituted or substituted by halogen; Y_(a) is —CH₂—, —C(O)—,—CH(OH)—, —C(═NOH)—, O or S, and R_(4a) is (C₄₋₁₄)alkyl or(C₄₋₁₄)alkenyl;

or a pharmaceutically acceptable salt or hydrate thereof;

-   -   Compounds as disclosed in WO02/06268A1, e.g. a compound of        formula VII

wherein each of R_(1d) and R_(2d), independently, is H or anamino-protecting group;

R_(3d) is hydrogen, a hydroxy-protecting group or a residue of formula

R_(4d) is C₁₋₄alkyl;

n_(d) is an integer of 1 to 6;

X_(d) is ethylene, vinylene, ethynylene, a group having a formula-D-CH₂— (wherein D is carbonyl, —CH(OH)—, O, S or N), aryl or arylsubstituted by up to three substitutents selected from group a asdefined hereinafter;

Y_(d) is single bond, C₁₋₁₀alkylene, C.₁₋₁₀alkylene which is substitutedby up to three substitutents selected from groups a and b, C₁₋₁₀alkylenehaving O or S in the middle or end of the carbon chain, or C₁₋₁₀alkylenehaving O or S in the middle or end of the carbon chain which issubstituted by up to three substituents selected from groups a and b;

R_(5d) is hydrogen, C₃₋₆cycloalkyl, aryl, heterocyclic group,C₃₋₆cycloalkyl substituted by up to three substituents selected fromgroups a and b, aryl substituted by up to three substituents selectedfrom groups a and b, or heterocyclic group substituted by up to threesubstituents selected from groups a and b;

each of R_(6d) and R_(7d), independently, is H or a substituent selectedfrom group a;

each of R_(8d) and R_(9d), independently, is H or C₁₋₄alkyl optionallysubstituted by halogen; <group a> is halogen, lower alkyl, halogenolower alkyl, lower alkoxy, lower alkylthio, carboxyl, loweralkoxycarbonyl, hydroxy, lower aliphatic acyl, amino, mono-loweralkylamino, di-C₁₋₄alkylamino, acylamino, cyano or nitro; and

<group b> is C₃₋₆cycloalkyl, aryl or heterocyclic group, each beingoptionally substituted by up to three substituents selected from groupa;

with the proviso that when R_(5d) is hydrogen, Y_(d) is a either asingle bond or linear C₁₋₁₀ alkylene, or a pharmacologically acceptablesalt, ester or hydrate thereof;

-   -   Compounds as disclosed in JP-14316985 (JP20023169851 e.g. a        compound of formula VII

wherein R_(1e),R_(2e),R_(3e),R_(4e),R_(5e),R_(6e),R_(7e), n, X_(e) andY_(e) are as disclosed in JP-14315985;

or a pharmacologically acceptable salt, ester or hydrate thereof;

-   -   Compounds as disclosed in WO031062252A1, e.g. a compound of        formula IX

wherein

Ar is phenyl or naphthyl; each of m_(g) and n_(g) independently is 0 or1; A is selected from COOH, PO₃H₂, PO₂H, SO₃H, PO(C₁₋₃alkyl)OH and1H-tetrazol-5-yl; each of R_(1g) and R_(2g) independently is H, halogen,OH, COOH or C₁₋₄alkyl optionally substituted by halogen; R_(3g) is H orC₁₋₄alkyl optionally substituted by halogen or OH; each R_(4g)independently is halogen, or optionally halogen substituted C₁₋₄alkyl orC₁₋₃alkoxy; and each of R_(g) and M has one of the significances asindicated for B and C, respectively, in WO03/062252A1;

or a pharmacologically acceptable salt, solvate or hydrate thereof;

-   -   Compounds as disclosed in WO03/062248A2, e.g. a compound of        formula X

wherein Ar is phenyl or naphthyl; n is 2,3 or 4; A is COOH,1H-tetrazol-5-yl, PO₃H₂, PO₂H₂, —SO₃H or PO(R_(5h))OH wherein R_(5h) isselected from C₁₋₄alkyl, hydroxyC₁₋₄alkyl, phenyl, —CO—C₁₋₃alkoxy and—CH(OH)-phenyl wherein said phenyl or phenyl moiety is optionallysubstituted; each of R_(1h) and R_(2h) independently is H, halogen, OH,COOH, or optionally halogeno substituted C₁₋₆alkyl or phenyl; R_(3h) isH or C₁₋₄alkyl optionally substituted by halogen and/OH; each R_(4h)independently is halogen, OH, COOH, C₁₋₄alkyl, S(O)_(0,1 or 2)C₁₋₃alkyl,C₁₋₃alkoxy, C₃₋₆cycloalkoxy, aryl or aralkoxy, wherein the alkylportions may optionally be substituted by 1-3 halogens; and each ofR_(n) and M has one of the significances as indicated for B and C,respectively, in WO031062248A2

or a pharmacologically acceptable salt, solvate or hydrate thereof.

-   -   Compounds as disclosed in WO 04/103306A, WO 05/000833,        WO05/103309 or WO 05/113330, e.g. compounds of formula XIa or        XIb

wherein

A_(k) is COOR_(5k), OPO(OR_(5k))₂, PO(OR_(5k))₂, SO₂OR_(5k),POR_(5k)OR_(5k) or 1H-tetrazol-5-yl, R_(5k) being H or C₁₋₆alkyl;

W_(k) is a bond, C₁₋₃alkylene or C₂₋₃alkenylene:

Y_(k) is C₆₋₁₀aryl or C₃₋₉heteroaryl, optionally substituted by 1 to 3radicals selected from halogene, OH, NO₂, C₁₋₆alkyl, C₁₋₆alkoxy;halo-substituted C₁₋₆alkyl and halo-substituted C₁₋₆alkoxy;

Z_(k) is a heterocyclic group as indicated in WO 04/103306A, e.g.azetidine;

R_(1k) is C₆₋₁₀aryl or C₃₋₉heteroaryl, optionally substituted byC₁₋₆alkyl, C₆₋₁₀aryl, C₆₋₁₀arylC₁₋₄alkyl, C₃₋₉heteroaryl,C₃₋₉heteroarylC₁₋₄alkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkylC₁₋₄alkyl,

C₃₋₈heterocycloalkyl or C₃₋₈heterocycloalkylC₁₋₄alkyl; wherein any aryl,heteroaryl, cycloalkyl or heterocycloalkyl of R_(1k) may be substitutedby 1 to 5 groups selected from halogen, C₁₋₆alkyl, C₁₋₆alkoxy and halosubstituted-C₁₋₆alkyl or —C₁₋₆alkoxy;

R₂k is H, C₁₋₆alkyl, halo substituted C₁₋₆alkyl, C₂₋₆alkenyl orC₂₋₆alkynyl: and

each of R_(3k) or R_(4k), independently, is H, halogen, OH, C₁₋₆alkyl,C₁₋₆alkoxy or halo substituted C₁₋₆alkyl or C₁₋₆alkoxy;

and the N-oxide derivatives thereof or prodrugs thereof,

or a pharmacologically acceptable salt, solvate or hydrate thereof.

The compounds of formulae III to XIb may exist in free or salt form.Examples of pharmaceutically acceptable salts of the compounds of theformulae III to VIII include salts with inorganic acids, such ashydrochloride, hydrobromide and sulfate, salts with organic acids, suchas acetate, fumarate, maleate, benzoate, citrate, malate,methanesulfonate and benzenesulfonate salts, or, when appropriate, saltswith metals such as sodium, potassium, calcium and aluminium, salts withamines, such as triethylamine and salts with dibasic amino acids, suchas lysine. The compounds and salts of the combination of the presentinvention encompass hydrate and solvate forms.

Acyl as indicated above may be a residue R_(y)—CO— wherein R_(y) isC₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl or phenyl-C₁₋₄alkyl. Unless otherwisestated, alkyl, alkoxy, alkenyl or alkynyl may be straight or branched.

Aryl may be phenyl or naphthyl, preferably phenyl.

When in the compounds of formula I the carbon chain as R₁ issubstituted, it is preferably substituted by halogen, nitro, amino,hydroxy or carboxy. When the carbon chain is interrupted by anoptionally substituted phenylene, the carbon chain is preferablyunsubstituted. When the phenylene moiety is substituted, it ispreferably substituted by halogen, nitro, amino, methoxy, hydroxy orcarboxy.

Preferred compounds of formula III are those wherein R₁ is C₁₃₋₂₀alkyl,optionally substituted by nitro, halogen, amino, hydroxy or carboxy,and, more preferably those wherein R₁ is phenylalkyl substituted byC₆₋₁₄-alkyl chain optionally substituted by halogen and the alkyl moietyis a C₁₋₆alkyl optionally substituted by hydroxy. More preferably, R₁ isphenyl-C₁₋₆alkyl substituted on the phenyl by a straight or branched,preferably straight, C₆₋₁₄alkyl chain. The C₆₋₁₄alkyl chain may be inortho, meta or para, preferably in para.

Preferably each of R₂ to R₅ is H.

In the above formula of VII “heterocyclic group” represents a 5- to 7membered heterocyclic group having 1 to 3 heteroatoms selected from S, Oand N. Examples of such heterocyclic groups include the heteroarylgroups indicated above, and heterocyclic compounds corresponding topartially or completely hydrogenated heteroaryl groups, e.g. furyl,thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, pyrrolyl, imidazolidinyl, pyrazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl orpyrazolidinyl. Preferred heterocyclic groups are 5-or 6-memberedheteroaryl groups and the most preferred heteocyclic group is amorpholinyl, thiomorpholinyl or piperidinyl group.

A preferred compound of formula III is2-amino-2-tetradecyl-1,3-propanediol. A particularly preferred S1Preceptor agonist of formula I is FTY720, i.e.2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in apharmaceutically acceptable salt form (referred to hereinafter asCompound A), e.g. the hydrochloride, as shown:

A preferred compound of formula IV is the one wherein each of R′₂ toR^(′) ₅ is H and m is 4, i.e.2-amino-2-{2-[4-(1-oxo-5-phenylpentyl)phenyl]ethyl}propane-1,3-diol, infree form or in pharmaceutically acceptable salt form (referred tohereinafter as Compound B), e.g the hydrochloride.

A preferred compound of formula V is the one wherein W is CH₃, each ofR″₁ to R″₃ is H, Z₂ is ethylene, X is heptyloxy and Y is H, i.e.2-amino-4-(4-heptyloxyphenyl)-2-methyl-butanol, in free form or inpharmaceutically acceptable salt form (referred to hereinafter asCompound C), e.g. the hydrochloride. The R-enantiomer is particularlypreferred.

A preferred compound of formula Via is the FTY720-phosphate (R₂, is H,R_(3q) is OH, X, is O, R_(1a) and R_(1b) are OH). A preferred compoundof formula IVb is the Compound C-phosphate (R_(2a) is H, R_(3b) is OH,X, is O, R_(1a) and R_(1b) are OH, Y_(a) is O and R_(4a) is heptyl). Apreferred compound of formula V is Compound B-phosphate.

A preferred compound of formula VIII is(2R)-2-amino-4-[3-(4-cyclohexyloxybutyl)-benzo[b]thien-6-yl]-2-methylbutan-1-ol.

A preferred compound of formula XIa is e.g.1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylicacid, or a prodrug thereof.

It will be appreciated that the compounds as described herein may be thedirect active substances, or may be prodrugs. For example, the compoundsmay be phosphorylated forms.

It has now been found that S1P receptor modulators have an inhibitory,preventative or delaying effect on conditions associated with ordependent on or affected by levels of BDNF.

In one particular aspect of the present invention, the compounds asdescribed herein, representing the genus of S1P receptor modulators,increase the levels of BDNF, for example, the compounds as describedherein stimulate BDNF production.

A compound which induces brain-derived neurotrophic factor (BDNF)expression can be used as a therapeutic agent for treatment of nervoussystem disorders and diseases, or treatment of diabetes mellitus.

More particularly, it is useful for nervous system injured by wound,surgery, ischemia, infection, metabolic diseases, malnutrition,malignant tumor, or toxic drug, etc. Especially, it can be used in thetreatment of conditions wherein sensory neurons or retinal ganglioncells are injured.

More especially, the compounds can be used in the treatment ofcongenital conditions or neurodegenerative diseases, for example,Alzheimer's disease, Parkinson's disease (the symptoms of Parkinson'sdisease may be caused by the degeneration of dopaminergic neuron),Parkinson-Plus syndromes (e.g., progressive spranuclear palsy(Steele-Richardson-Olszewski syndromes), olivopontocerebellar atrophy(OPCA), Shy-Drager syndromes (Multiple Systems Atrophy), and Parkinsondementia complex of Guam), Huntington's disease (Huntington's chorea),and Rett Syndrome, but are not limited thereto.

Further, the compounds can be used in the treatment of sensory nervedysfunction and congenital diseases or neurodegenerative diseases beingassociated with degenerative of retina.

In addition, the the compounds can be used in the treatment of inheritedconvulsive paraplegia associated with retina degeneration (Kjellin andBarnard-Scholz syndromes), retinitis pigmentosa, Stargardt disease,Usher syndromes (retinitis pigmentosa accompanied by congenital hearingloss) and Refsum syndrome (retinitis pigmentosa, congenital hearingloss, and polyneuropathy).

Further, the compounds can be used to treat obesity.

The compounds may also be used to treat cognitive impairment and/orattention deficit disorder, for example deficits and abnormalities inattention and vigilance, executive functions and memory (for instanceworking memory and episodic memory). Other disorders relating tocognitive dysfunction include sleep related breathing disorders (SRBD),behavioral impairments, information processing deficits and age-relateddisorders, Attention-deficit hyperactivity disorder (ADHD), childhoodADHD, adult ADHD, excess daytime somnolence, sleep apnea, traumaticbrain injury, neurodegenerative disorders with associated memory andcognitive problems (such as Alzheimer's disease, Lewy body dementia,senile dementia, vascular dementia, Parkinson's disease), chronicfatigue syndrome, fatigue associated with sleep deprivation or prolongedwakefulness, age-related decline in memory and cognitive function (suchas mild cognitive impairment), cognitive impairment associated with mooddisorders (such as depression) and anxiety, schizophrenia, day timesleepiness associated with narcolepsy.

In addition, the compounds can be used to treat sleep disorders, e.g.narcolepsy, primary insomnia, sleep-awake rhythm disorders (e.g.,work-shift syndrome, time-zone syndrome (jet-lag)).

In additions, the compounds can be used to treat depressive disorder,e.g. manic-depressive psychosis.

In a further use, the compounds can be useful in making patients feelbetter.

In a series of further specific or alternative embodiments, the presentinvention provides:

-   -   1.1 A method for preventing, inhibiting or treating a condition        effected by BDNF production, in a subject in need thereof,        comprising administering to said subject a therapeutically        effective amount of an S1P receptor modulator, e.g. a compound        of formulae I to XIb.    -   1.2 A method for alleviating or delaying progression of the        symptoms of obesity, a sleep disorder or depressive disorder, in        a subject in need thereof, in which method the BDNF-dependent        factor associated with said disease is prevented or inhibited,        comprising administering to said subject a therapeutically        effective amount of an S1P receptor modulator, e.g. a compound        of formulae I to XIb.    -   1.3 A method for inducing the production of BDNF, in a subject,        comprising administering to said subject a therapeutically        effective amount of an S1P receptor modulator, e.g. a compound        of formulae I to XIb.    -   1.4 A method for slowing progression of obesity, a sleep        disorder or depressive disorder, in a subject, in which method        the BDNF-dependent factor associated with said disease is        prevented or inhibited, comprising administering to said subject        a therapeutically effective amount of an S1P receptor modulator,        e.g. a compound of formulae I to XIb.    -   1.5 A method as indicated above, wherein the S1P receptor        modulator is administered intermittently.        -   For example, the S1P receptor modulator may be administered            to the subject every 2^(nd) or 3^(rd) day or once a week.    -   2. A pharmaceutical composition for use in any one of the        methods 1.1 to 1.5, comprising an S1P receptor modulator, e.g. a        compound of formulae I to XIb as defined hereinabove, together        with one or more pharmaceutically acceptable diluents or        carriers therefor.    -   3. An S1P receptor modulator, e.g. a compound of formula I to        XIb as defined herein above, for use in any one of the methods        1.1 to 1.5.    -   4. An S1P receptor modulator, e,g. a compound of formulae 1 to        XIb as defined herein above, for use in the preparation of a        medicament for use in any one of the methods 1.1 to 1.5.

Utility of the S1P receptor modulators, e.g. the S1P receptor modulatorscomprising a group of formula Y, in preventing or treating a diseaseassociated with BDNF as hereinabove specified, may be demonstrated inanimal test methods as well as in clinic, for example in accordance withthe methods hereinafter described.

EXAMPLE 1 In Vivo: S1P Receptor Modulator Induced BDNF Production

Female DA rats were treated for 9 days (5 days, 2 day pause, 4 days)with FTY720 p.o.

Expt 1: 0.3 mg/kg/d vs. vehicle.

N=3 rats/group

One day after the last treatment, the rats were perfused with ice-coldPBS and different CNS regions were isolated.

The results are shown in FIG. 1.

EXAMPLE 2 In Vivo: S1P Receptor Modulator Induced BDNF Production

Female DA rats were treated for 9 days (5 days, 2 day pause, 4 days)with FTY720 p.o.

0,1; 0.3 or 1 mg/kg/d vs vehicle

N=3 rats/group

One day after the last treatment, the rats were perfused with ice-coldPBS and different CNS regions were isolated.

The results are shown in FIG. 2.

EXAMPLE 3 In Vitro: S1P Receptor Modulator Induced BDNF Production

Effect of FTY720 on BDNF expression in cultured CTX, STR, and HIPneurons was investigated.

Neurons were treated with phosphorylated FTY720 (FTY-p) (1 and 10 nM)for the last 6 days.

Cell lysates were collected at 21 days in vitro,

axis indicates levels of BDNF normalized to control.

*P<0.05 vs DMSO

The results are shown in FIGS. 3A, B and C.

EXAMPLE 4 In Vitro: S1P Receptor Modulator Induced BDNF Production

Effect of FTY720 on BDNF expression in cultured CTX and HIP neurons wasinvestigated.

Neurons were treated with FTY720 (FTY-p) (0.01, 0.1, 1 and 10 nM) forthe last 6 days. Cell lysates were collected at 21 days in vitro.

Y axis indicates levels of BDNF normalized to control.

The results are shown in FIG. 4.

EXAMPLE 5 Clinical Trial: S1P Receptor Modulator made People Feel Better

In a 6-month, placebo controlled, Phase II trial involving 281 patientswith relapsing MS, FTY720 reduced gadolinium-enhanced magnetic resonanceimaging (MRI) lesions by up to 80%, and the annualized relapse rate bymore than 50%, compared with placebo, at doses of 1.25 and 5 mg oncedaily.³ The resulting low disease activity on both MRI and relapses wassustained in patients treated with FTY720 for up to 24 months during adose-blinded extension phase. Patients who received placebo also hadmarked improvements after switching to FTY720 in the extension.

In this study, depressive symptoms were assessed by means of the BeckDepression Inventory second edition (BDI-II). These results arepresented here.

Method

Patients with relapsing MS (relapsing-remitting or secondaryprogressive) were randomized to receive placebo or FTY720 1.25 or 5mg/day, for 6 months (the core study). At the end of this period,placebo-treated patients were re-randomized to one of the two FTY720doses, while those originally randomized to FTY720 continued treatmentat the same doses. After approximately 18-24 months, patients receivingFTY720 5 mg, were switched to 1.25 mg in view of evidence that thehigher dose conferred no efficacy benefit over the lower dose.

The BDI-II was administered at baseline, and at 3 and 6 months duringthe core study and at 12 and 24 months during the extension phase (i.e.6 and 18 months after the start of the extension phase). This is a21-item self-report scale measuring various symptoms and attitudesassociated with depression. Respondents rate depressive symptomsexperienced during the past two weeks on a 4-point scale, coded 0 to 3by increasing order of severity. A total score across all 21 items canbe generated, with lower total scores indicating lower overall severityof depressive symptoms. BDI-II total scores of 14 or above areindicative of clinical depression. Ny reduction in the BDI-II scoreindicated an Improvement in depression.

Results

Patients

Of the 281 patients originally randomized to treatment, 255 completedthe core study. BDI-II scores at baseline and 6 months were available in239 patients.

Changes in BDI-II Scores During the Core Study

Mean BDI-II scores during the core study are shown in FIG. 5, andchanges in these scores from baseline during the core study are shown inFIG. 6. BDI-II scores decreased from baseline in patients receivingFTY720 1.25 mg/day, remained consistent in patients receiving FTY720 5.0mg/day, and increased in patients on placebo. At 6 months, the change inBD-II scores from baseline in FTY720 1.25 mg/day treated patients wassignificantly greater than in placebo-treated patients. The differencein changes in BDI-II scores between the two doses of FTY720 was notsignificant at the 5% level.

1. A method for preventing, inhibiting or treating a condition effectedby BDNF production, in a subject in need thereof, comprisingadministering to said subject a therapeutically effective amount of anS1P receptor modulator, e.g. a compound of formulae I to XIb as definedhereinabove.
 2. The method of claim 1, where the condition affected byBDNF production is selected from one or more of diabetes, nervous systeminjured by wound, congenital conditions, neurodegenerative diseases,sensory nerve dysfunction, obesity, cognitive impairment, attentiondeficit disorders, sleep disorders or depressive disorders.
 3. A methodfor inducing the production of BDNF, in a subject, comprisingadministering to said subject a therapeutically effective amount of anS1P receptor modulator, e.g. a compound of formulae I to XIb.
 4. Amethod for making a patient feel better, e.g. by removing symptoms ofdepression, comprising administering to said subject a therapeuticallyeffective amount of an S1P receptor modulator, e.g. a compound offormulae I to XIb.
 5. A method according to claim 1, wherein the S1Preceptor modulator is administered intermittently.
 6. A pharmaceuticalcomposition for use in a method according to claim 1, comprising an S1Preceptor modulator, e.g. a compound of formulae I to XIb as definedhereinabove, together with one or more pharmaceutically acceptablediluents or carriers therefor.
 7. A method according to claim 1comprising co-administration, e.g. concomitantly or in sequence, of atherapeutically effective non-toxic amount of a S1P receptor modulatorand a second therapeutic substance.
 8. A pharmaceutical combination,e.g. a kit, comprising a) a first agent which is a S1P receptormodulator e.g. a compound of formulae I to XIb as defined herein above,in free form or in pharmaceutically acceptable salt form, and b)instructions for use in a BDNF-related condition or disease, asdescribed herein.
 9. The combination of claim 7, wherein theBDNF-related condition or disease selected from one or more of diabetes,nervous system injured by wound, congenital conditions,neurodegenerative diseases, sensory nerve dysfunction, obesity,cognitive impairment, attention deficit disorders, sleep disorders ordepressive disorders.
 10. A method according to claim 1, wherein the S1Preceptor modulator is 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diolin free form or in a pharmaceutically acceptable salt form.